Thank you everybody for coming. I'm David Connolly here at Rhythm Pharmaceuticals, and thanks for coming to our R&D event this morning. We issued a press release today that provides details on today's update on MC4R pathway programs, and it is available on our website. Our forward-looking statements disclosure slide here on slide two. Please read them. And with that in mind, I'll remind you, this event contains remarks concerning future expectations, plans, prospects, which constitute forward-looking statements. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual or quarterly reports on file with the SEC.
In addition, any forward-looking statements represent our views only as of today, and should not be relied upon as representing our views as of any subsequent dates, and we specifically disclaim any obligation to update such statements. As a brief overview of today's event, I'll briefly introduce each of today's speakers and run down our agenda. Dr. David Meeker is Rhythm's Chairman, CEO, and President. Dr. Jennifer Miller, a professor of pediatric endocrinology from the University of Florida, and then Amy Wood, Executive Director and Co-founder of the Raymond A. Wood Foundation, a parent and patient-led rare disease patient advocacy organization dedicated to empowering survivors of craniopharyngioma and hypothalamic-pituitary brain tumors. Each will discuss the landscape for hypothalamic obesity, followed by a Q&A, which will be moderated by David. And then we will hear from Dr.
Dorit Koren, Medical Director in Clinical Development here at Rhythm Pharmaceuticals, and Patrick Sleiman, PhD, Director of Genetics and Translational Research and Development at Rhythm. Doctors Koren and Sleiman will discuss data and the genetics behind them from Rhythm's exploratory Phase 2 DAYBREAK trial. Then we'll also hear from Danica Grujic, PhD, Senior Director of Non-Clinical Development here at Rhythm in Translational Research and Development. She will provide an introduction to RM-718, Rhythm's new MC4R agonist drug candidate, and Dr. Meeker will present top line data from our Phase 3 pediatrics trial of setmelanotide. Then we'll conclude with a Q&A. For our sell-side analysts who cover Rhythm, participating via the webcast, there will be a chat function through which you can submit questions, and we will read them aloud here. And then with that, I'll turn the call over to Dr. Meeker.
All right, thank you, Dave, and thanks to all of you for showing up on a snowy morning, and hello to all of you tuning in on the web. So Dave ran through the agenda for the morning. I'm going to provide a brief intro, further intro into what you're going to hear today. So thinking back, Rhythm, founded in 2008, first patient treated, I think, in the early teens. And when we treated that first POMC patient, it was like, wow. We kind of had no idea where it was going, but it was a pretty dramatic response in a world where obesity medicines don't usually have much effect. That was quite a bit pre-GLP-1s. But beyond that, we didn't know a lot.
We didn't know how big this was going to be. We didn't know, where else we might go in the pathway. We really didn't even know if there were going to be a lot of those patients, some POMC and leptin receptor biallelics. I think we've learned, there's probably a fair number out there. They're pretty hard to find. Those numbers are small, but, but that's where we started, and, what you're going to hear today is that, this has really opened up, and our understanding of the science is continuing to grow, and the more we get that understanding, of course, more doors, do open. A lot of it's about the genetics.
It's very much focused around the pathways we'll talk about, but, understanding the genetics of that pathway, and then, you know, we're going to move with 718, but not just 718, the pediatric program. You know, commitment to lifecycle management, expanding it, and making sure that patients who need this drug can not only get the drug, meaning all, all patients, all ages, but also get it in the best possible form, the most convenient form, the safest and most effective form. So again, continuing to work on lifecycle management. It's been a good year for Rhythm, a good couple of years. I think, we've talked on our other calls about, the commercial execution, that continues to go well.
The hypothalamic obesity programs, which are an area of huge interest and focus, for all of us, no matter where you sit, we understand that. Those trials continue to progress. And then today, we're going to talk about, you know, the rest of the development program here. We're not talking about EMANATE today. We'll come back at a later point in 2024 to talk more about that. But, EMANATE taught us a lot. I mean, that initial, you know, attempts to understand other genes, how do we do that? How we do well? We made some mistakes, we did some things well. So that's also been a learning process for us. Our favorite cartoon.
I'm sure your favorite cartoon, if you're not sick of seeing this already, but it's, it's the anchor. It's just, highlights again, that, you know, we're all about the pathway, but, you know, in the beginning, it was the POMC neuron. I think increasingly we're understanding that, yeah, the hypothalamus is a complex, part of the brain. You've got multiple pathways. GLP-1s have continued to highlight, you know, there's different sites of action and, how do all these things interact, you know, what's inhibiting, what's activating? And so, our, you know, understanding of that, again, as you'll hear through some of these, the genetic work we're doing is growing.
All of that's translating into the downstream effects, which is, you know, patients who do have impaired signaling to the POMC pathway, as we know, have a deficit in alpha melanocyte-stimulating hormone. Again, this has been really one of the fundamental pieces we've just tried to reinforce, which we're not disrupting normal physiology with a pharmacologic intervention. We're replacing a deficit with a hormone. Setmelanotide is an analog of alpha melanocyte-stimulating hormone... what is deficient in a setting of POMC signaling impairment. So, the downstream part, the hyperphagia, again, it, I think I can use myself as an example. I mean, that's just hungry, and, you know, we all know what hunger means.
The reality is, no, I had no idea, you know, how complicated hunger is, and the idea of what we experience when we miss a meal, and what an individual who has an impaired pathway experiences when, despite eating, they just cannot feel satiated. They just continue to be preoccupied by food. And so not only our understanding of that, but trying to help the world understand that because all parts of the healthcare system are starting with that very fundamental. And it's the doctors, I think, are the worst of all, due respect to any doctors in the room, you know, who in terms of really understanding the different, you know, aspects of that. What is it that's different about hyperphagia from just regular hunger?
And then energy expenditure, the yin yang of this whole thing, which is the dual curse here that these patients suffer from. Not only are they endlessly hungry, but their body's slowing the metabolic rate because they think they're just, you know, no food's on board. So, opportunities, again, you know the numbers on Bardet-Biedl is a very real opportunity. We're working that. Hypothalamic obesity, we'll hear more about, but larger number of patients. But again, the majority diagnosed, you know, talking with Amy, and maybe Amy will comment on this a little bit, they're probably underdiagnosed. I mean, Jennifer, you know, Dr. Miller, I know this as well. And so I think, again, we're early in this whole process, and so a lot more to be learned there.
Then the EMANATE genes, which do open up a much larger opportunity and, and, again, a work in progress as we go through this. So what you'll hear today, again, Dr. Miller and, Amy Wood, again, you know, you've, you've endlessly seen the, the graphics. I'm gonna show you that graphic one more time 'cause I like the graphic, but there, Dr. Miller is taking care of these patients, living with these patients. She was lead investigator in our, phase two trial. She's an active investigator in our phase three effort here. So enormous experience, not only pre-potential treatment, but, but also seeing the impact the treatment can have. And, and Amy, as Dave highlighted, living, you know, with, her son, affected by this and, and motivated to start the Raymond A. Wood Foundation
S o not only having a personal experience, but also being a leader in the community and hearing all of the other stories of families and patients who are struggling to deal with this. The exploratory Phase 2 DAYBREAK trial, again, we'll think that's gonna be really interesting. As I've told a couple of you, press release is really hard to convey a complex study like that and these preliminary results in a press release. So hopefully, you'll leave this meeting with a better understanding of what we saw there. I'm, I'm excited about it. I think there's, there's something there. It's not, it's not gonna be a simple straight shot, but I think we've got some ideas about ways to think about paths forward here.
RM-718, again, we talked about, but you'll see why we're, we feel really good about that. And then, the Phase 3 pediatric trial, we'll finish with that. It's, we're confirming in a sense, what we've demonstrated previously, but it's, there's some really striking things about that trial, and one of it is just the severity of kids at such an early age. I mean, it's almost unimaginable how affected you can be so quickly. So, brief intro to our hypothalamic session. Talked about the numbers. You're gonna hear more from Dr. Miller about this whole disease.
Like I said, I'm not gonna leave without showing the graphic again, 'cause I just think it's a good graphic and that this hypothalamic obesity world hasn't had the, I wouldn't call it a luxury, but hasn't had the benefit of a therapy that could make a difference. So as you remember, we had the 16-week data with 18%. So this is on the 12. So we had 18 patients. You remember the disposition, we took it through. 14 patients went into the long-term extension. On our poster, we all 14 are still in the trial, so we haven't lost anybody. We've had people bounce in and out a little bit, but they've come back. And in coming back, it's very clear when you're off the drug, you regain your weight.
When you go back on the drug, you lose it again. So, and Dr. Miller has one of those patients, so she can comment if she wants when she gets up. But, and then over six and 12 months, you know, that...those 12 patients, you know, continue to deepen. But not everybody, and this is one of the things where, you know, trying to get off this concept that it's just endless reductions in BMI is the end game here, 'cause obviously that's not the end game. The end game is to restore people to some level of normal functioning, whatever that BMI is for that patient. And so, we have patients in this trial whose BMI is increasing after a very dramatic... Best example is a 6-year-old whose BMI is less than 50th percentile. It's increasing.
It's no longer driving the mean BMI down. It's driving the mean BMI up, thank God, because you would want that child to be gaining weight and doing it. And then, as we know, BMI in children is not a great metric. So looking at things like this, BMI Z, the basically, your standard deviations away from normal. So 2.5 as a starting point, very severe, decreasing to 1.5 at 12 months. Anything over 0.2 is felt to be clinically meaningful. And then another metric that people are also very interested in is the percent of the 95th percentile. So what percentage above that 95th percentile are you? So 145% of the 95th, and decreasing almost to 104.
So more and more, we'll be looking at, you know, can we get people back to normal? And normal may or may not be on a normal BMI growth curve. BMI may be their prior, that patient's set point. In other words, where would they have lived if they had not developed this complication? ... And this is the individual, and as you can see, the red bars are the. I'm sorry. The red bars are the 12-month. And, you know, essentially, everybody has had a further deepening, or if they had a significant deepening, they've maintained that. And with the exception of one patient here who had a very good response and has had some regression back, but still maintains a significant change from baseline. It's a teenager also continuing to grow. So with that, I'm gonna...
Oh, and this is our Phase 3 trial that you know is ongoing, 120. We're close to the end of getting all of our patients screened and ready to enroll. So, 120 patients randomized two-to-one, with, and then that'll be followed, 52-week trial, followed by an open-label extension. So with that, I'm going to invite Dr. Miller up, who Dave introduced already. But I've had the pleasure of getting to know Dr. Miller, and I will add only to the fact that professor of medicine at the University of Florida. But, one of the most passionate people, I've had the opportunity of getting to know about what you do, and thank you.
Thank you. Hi. So I'm gonna just... you heard a little bit about the hypothalamic obesity program, and so, you know, the hypothalamus and pituitary are sort of the master glands of our bodies, right? They sit in the middle of the brain, but they control everything, especially the hypothalamus controls, you know, sleep, your sleep-wake cycle, your pain cycle, your, you know, heat-cold tolerance, and all of your hormones from your pituitary, all of your endocrine hormones. And so tumors that disrupt the hypothalamic pituitary area or the pituitary stalk result in a myriad of complications for people who have had resection of these tumors, or even we're finding out now, even with just proton beam radiation targeted at the tumors, you can still see profound injury to the hypothalamic pituitary region.
This is, you know, complete panhypopituitarism, so they need complete hormone replacement and in reduction in metabolic rate, and also in about 50% of cases, hypothalamic obesity that starts immediately after surgery. You know, to sort of describe it to you, it's—I'm gonna show you a video in a minute, but these patients wake up in the PACU, and they believe that the nurses there are, they're waitresses, and they immediately, as soon as they're awake from anesthesia, say, "I'd like a cheeseburger, french fries, and a milkshake." And then they go up to the ICU, and they eat stacks and stacks of pancakes.
You know, the thing is, is that, you know, we were talking earlier, Amy and I, about whether or not people tell parents about this potential complication or talk about it, and, and I believe that they do. But in the midst of being a parent of a child with a brain tumor, all you hear is brain tumor, and that's it. You don't think about these other issues. As a physician taking care of these patients, you're worried about all the endocrine complications that are happening postoperatively. You know, they get central adrenal insufficiency, so they have cortisol deficiency, which could kill them. They have diabetes insipidus, which is issues with sodium and water balance, which could kill them.
So as physicians, we're not really attending to the fact of the appetite regulation and/or the weight gain, which can be quite remarkable, and I'll show you that on a graph in just a minute. That's the Rhythm slide that you all know. The idea behind hypothalamic obesity being a target for setmelanotide is that the physical injury to the hypothalamus actually ends up resulting in blockage of the downs, but the upstream, downstream signals getting to the melanocortin 4 receptor. So therefore, it cannot out-activate out the MSH, which then means there's no satiety. So, we know with hypothalamic injury that you get a leptin resistance, and so leptin, which is a satiety hormone, cannot get through as well and bind to its receptors in the hypothalamus. Same thing happens with insulin.
Insulin can't bind to its receptors as well, probably because of physical injury to the hypothalamus. So when you can't bind these satiety receptors to start the activation of this pathway, then downstream, of course, you develop hyperphagia. So one of the biggest problems that we see in pediatrics is that craniopharyngiomas are really a zebra. This is the most common type of brain tumor that causes hypothalamic obesity in children, but often because these are children, they're often young children, and the symptoms are kind of, you know, nebulous. You get a headache, you vomit, you know, you gain or lose weight. They're often humongous by the time that they're diagnosed and disrupt a huge portion of the hypothalamic pituitary region.
So you know that when they're already physically that big, you're, you're gonna be in trouble in terms of how much hypothalamus and pituitary function you have left postoperatively or post-radiation. All right, so this is my video to show you hypothalamic obesity and what it really is like. Maybe. Oh, I have to hit it?
I wanna eat! I'm hungry, Mama. Please, what I eat? I'm so hungry. Mama?
It's constant and unrelenting. When a kid is this age, there's no reasoning with a child who's hungry. Can you imagine, as a parent, having to tell your child who is starving, "No, you can't eat because you can't. The doctors say you're already too fat, and you're, they're, you know, giving me grief about your weight." You know, and so when you're restricting diet in a child who's hungry, it becomes even worse. And so... it really is nonstop. Kids get up at night to seek food because they wake up, and they're starving. You know, they will steal food from other people. They'll eat garbage. They'll eat anything they can get their hands on, unfortunately, because they are so hungry.... Oh, that's not what I meant to do. I meant, sorry. There, okay.
So as we talked about, you can see here a growth chart. I'm gonna show you a bunch of growth charts of a person who had his craniopharyngioma removed at age 8, and you can see that within the first month... Where's my little pointer, Gilly? Where's the pointer? Within the first month here, look at this. 20-pound weight gain in the first month in the hospital. So most of these kids are in the hospital for 2-6 weeks in general, managing all the endocrine issues, and this is the amount of weight gain. It's quite stunning. You never see this in any other condition this quickly, and you can see how quickly it continues to go up until it's above the, you know, way above the chart, and so you no longer can see how much it's going up.
So there's multiple conditions that can lead to this. I speak mostly of craniopharyngioma because it's the most common, about 62%, but other children with other types of tumors are enrolled in the Phase 2 clinical trial. Kids with astrocytomas, hypothalamic hamartomas. These can all cause hyperphagia and decreased metabolism, so hypothalamic obesity, and so we include all of them. There are other causes as well, genetic causes, congenital brain malformations that we see as endocrinologists, causing hypothalamic obesity that I think are a little bit more difficult to treat, especially genetics, without pre-Rhythm, without the genetic testing that existed to help identify. Now, we can identify more of the genetic etiologies of these conditions. So this is the little boy I just showed you, who was saying how hungry he was, and so here he is.
Tumor removal was at age three, and you can see I've put both weight and BMI chart on here, and you can see that again, his weight went up 20 pounds in the first month. I mean, it was just insane and continued to go up. And then and here he is, BMI, same thing, going up, up, up, and so, so it's just... It's unrelenting. And can you imagine, again, you're a four-year-old, you know, and doctors shame you for this as parents. You know, they say: "Well, what are you doing? What are you feeding him? How are you? Why? You know, clearly, the child's eating too much." But the metabolism sucks afterwards, you know, because hypothalamic damage changes your metabolic rate, and also, you know, they are starvingly hungry.
So there is really, right now, no treatment algorithm for people with hypothalamic obesity. Most endocrinologists start with metformin. We know that children with hypothalamic obesity do have high insulin levels postprandially, and metformin is an insulin sensitizer, so we feel like: Okay, well, maybe we can prevent them from getting type 2 diabetes as a result of their obesity and these, these high insulin levels. So we put them on metformin. It does nothing, but it makes us feel better as doctors that we're trying something. And so almost everybody, I would say, with hypothalamic obesity, has been tried on metformin at some point in time. And then after Vyvanse got approved for treatment of binge eating disorder, stimulants became more common, for use in this condition, and so we try those as well.
Those cause some initial weight loss, but then subsequently, the weight tends to stabilize on those medicines. And they have orlistat on here, which is almost never used, especially in the pediatric population, because it causes you to excrete extra fat in your diet, in your stool. So it makes you have oily stools and leaky farts, so not a good thing. So nobody likes that as a kid. But, like, more than 25% of these individuals are on multiple medications to try to manage the symptoms of this condition because it's really hard.
So obviously, the newest kid on the block, as Dave mentioned, is the GLP-1s, and the GLP-1s, GIPs, have been tried now for the past few years in people with hypothalamic obesity, and this is just a growth chart of one of my patients who started on, at her highest, started on Vyvanse max dose. It did bring the weight down, as you can see, by about 20 pounds, or so, and this is BMI actually, this is not weight. So, this is the BMI curve because, in children, weight for height, well, in adults, weight for height matters. So it did bring her BMI down because it brought her weight down, but she's growing, developing individual, and so weight kind of stabilized at the 95th to 97th percentile. She's a 14-year-old girl. That's not good.
You know, I mean, when kids are heavy, kids are mean, and, and so she was really struggling. Like, we were pleased that she was back on the chart, BMI-wise. She was not, because she was still hungry all the time. She was really struggling to maintain that weight. She was going to the gym every day to work out, and she was restricting her diet, and she still couldn't lose the weight that she wanted to lose, so we put her on a GLP-1. The problem with GLP-1s is, as I mentioned, this is my thought at least, is GLP-1s work in two ways, right? They work in the periphery to decrease gastric or delay gastric emptying, so that you're supposed to feel full longer, and they work by hitting receptors in the hypothalamus to signal satiety.
Well, if your hypothalamus is damaged by surgery, then those receptors are likely either not there because they've been damaged or maybe just don't work as well because they've been damaged by the tumor. And so what we see with GLP-1s traditionally is this. You see about 20 pounds of weight loss maximum, and we think about—I would say most endocrinologists who have done this for a while say that about 10% of people with HO respond to GLP-1, so it's a, it's a pretty low percentile, but what I maintain, because I've been doing this a long time, is that that weight does not hold. It doesn't stick. They don't continue to lose weight on those medicines. And again, I believe it to be a problem with the receptors in the brain. The reason they lose weight, though, is very interesting.
So delayed gastric emptying, they also—remember, they don't feel full, so they will eat and eat, and then they will throw up because their stomach gets so stretched out by how much food they've put in it, and the longer you're delaying emptying, the more food you're putting in there, the more likely you are to throw up. So GLP-1s are very, very unfortunately miserable for this population, because it results in a ton of nausea and vomiting, which we have a really hard time controlling, even with things like ondansetron. And in general, most people, if they continue on it, it's only because they just want to maintain, you know, but, but they, they're not happy about it because it's, it's a miserable existence for most of them because they're throwing up a lot. So this is just a case report.
I'm gonna show you a picture of this young lady in just a second, but she had her craniopharyngioma resected at eight years of age. She gained about a pound a week. Postoperatively, multiple treatment trials were tried. We used diet, exercise, you know, famous metformin, and we initiated liraglutide. At the time, that was what was available, and the newest one, and she lost about 20 pounds. She maintained her weight over about the next 12 months, and then it began to increase over time. We changed her to tirzepatide when it became available because it's stronger, you know, GLP-1, GIP-1, and she had no additional weight loss on that. Didn't touch it. And so then she enrolled in the HO trial, which is the Phase 2 trial.
So here is where the GLP-1 was initiated, or yeah, GLP-1 was initiated here, tirzepatide initiated here, this one, and when she was up at her highest, Rhythm came along with Phase 2, and we enrolled her in the Phase 2. And this is what happened. Straight line down. It's like she hit a wall. So you can see here, this little arrow here means that it's going out past age 20. And so she is now, she's now almost 21 years of age. She's been on this for... close to January, it will be 2 years. And you can see here, this is her weight, but her BMI has done the exact same thing. It's just come down, down, down, which you didn't see, and you don't see with any of the other medicines that we've ever tried.
So it's really quite remarkable. And here she is. I mean, when you look at her, she is—she doesn't look all that heavy overall, but she is a teenage girl. This was extremely uncomfortable for her, because she was teased and made fun of and whatever, and was having to restrict her diet so much. Now, she's in college. She's living in a dorm. She couldn't even drive before. Her parents wouldn't let her drive because of the food stuff. They were worried that she was gonna go get food, and so they would drive her everywhere. But now she's living an independent life as an adult person, which is what an adult person should do. But these individuals with this condition could not do that without setmelanotide. And just one more, 'cause I love pictures, because I think pictures tell a thousand words.
Travis, he was at 20. I was with him when he got his astrocytoma resected. It was 9/11. I'll never forget it because we watched it happen together in the ICU while he was recovering. I followed him throughout his entire life. He would come in and say, "Dr. Miller, I don't understand. I'm not eating that much. I, you know, I don't have hyperphagia, but I'm gaining all this weight." When the opportunity for all three came along, I enrolled him, thinking I bet he does have hyperphagia, and he just doesn't know it, or he's not admitting to it, but really, it was his metabolism, honestly. Remember that this condition, once you treat it, will slow metabolism down quite significantly. So even with really minimal changes to his diet, here he is last month.
His BMI is down close to normal now. It's 32 from 52 when he started a year and a half ago. He, he told me he was able to travel for the first time recently because he could sit in a plane seat, and he didn't have to have a seatbelt extender. He was, for the first time ever, able to sit in a regular plane seat and not have to have a seatbelt extender. That, I mean, that. I know it sounds silly, but it's huge quality of life things for these people that, you know, they don't travel because it's uncomfortable, and it's terrible to have to get two plane seats and have to have the. They say it's embarrassing, you know?
But to be able to live his life, he has a girlfriend, he's getting a master's degree right now, which he will finish this month, and he's working with Marci to write a new hypothalamic obesity cookbook for people who are on setmelanotide. And so, but anyway, that's just a. I love this picture because it's close to the same shirt, you know, and you can really see the difference. And I really think, just look at the smile on his face. I mean, that's, as David mentioned, this is not just weight loss, right? It's weight loss is great, but the other effects, these freeing effects that this drug has, it's life-changing for these people. That's all I got.
Good morning. I just wanna thank my Rhythm colleagues for inviting me here today to share with you a little bit of the perspective of living with HO as a caregiver and for my son, Alex. So just starting off with talking a little bit about Alex's journey. So Alex, birth to four years old, was a neurotypical child. We didn't know he had any health issues. He was leading a great four-year-old life. He was full of energy, had lots of friends, was enjoying pre-K. One Thursday morning, we woke up, business as usual, but I noticed something was different about his left eye. It seemed to be drifting inward. So I was like: "That, something's going on." But we have a history of lazy eye in my family, so I was like, "Maybe I just haven't noticed." So I made an appointment.
Otherwise, he seemed fine. I made an appointment with an eye doctor and sent him off to school. As the day progressed, his teacher contacted me and said, "Have you noticed the eye?" And I said, "Yes, he has an eye doctor appointment." She said, "He's walking unsteady." And I was like: That's odd. So I made an appointment that afternoon with his pediatrician, brought him in, and the pediatrician said to me, "You need to take him to Johns Hopkins ER and get an MRI. I think it's a brain tumor or brain cancer." That was the most pivotal moment of our lives because that was where literally everything changed. So we got to Johns Hopkins ER that night.
They put him in an MRI, and they said, "He has a mass in the middle of his brain, and we're gonna have to operate immediately." So the next 24 hours, Alex was in the OR. He came out. We sort of thought that he was gonna be okay because they said it's a benign brain tumor. And you can kinda see in these pictures, this was this very week. We had gone to the strawberry patch. You know, he was doing normal things that week, and then here we are towards the end of the week and one week later. So, they told us it was a craniopharyngioma.
Dr. Miller touched on, you know, what a cranio is, but they said, "It's a benign tumor." So we sort of had the impression that we were going home in a couple of days, and he was gonna be fine, and how lucky were we? It's benign. Well, unfortunately, as the days progressed, we quickly learned that he was facing a host of issues. And, you know, just... I think Dr. Miller did a good job explaining cranio, but one of the things that I think, we talk about from the foundation perspective is from a neurosurgery perspective, it is one of the most difficult brain tumors to treat because of its location in the brain. And Alex spent four weeks in the PICU and weeks after at the rehab hospital.
Then the year after, we had multiple ER visits, med flights, and admissions for seizure and hypothermia. This is because benign is not fine. We say that all the time, but it's, you know, this tumor is almost mischaracterized because it's so it has so much impact on the brain. He developed panhypopituitarism, so complete loss of endocrine function, adipsic diabetes insipidus. This is the brain's inability to manage the body's water balance, coupled with no thirst mechanism. So his hypothalamus was damaged in a way that he can't sense thirst to even be able to manage his body fluids. He had adrenal insufficiency, as Jennifer talked about, and growth hormone deficiency. If a brain tumor and all that's not enough, we started to notice that he was beginning to gain weight immediately after surgery.
He went into the hospital at 40 pounds, and he left the hospital at 60 pounds. Alex didn't have much of an appetite prior to surgery. He was a picky eater. I was always struggling to get him to eat. After surgery, he tried to eat a napkin, and I was like: "This is... Something's going on." It was later on, maybe about two or three months later, where he received the formal diagnosis of hypothalamic obesity. But doing my research, I'm a researcher on these things, I had already seen that this could be an issue, and so started to kind of have these conversations with his doctor. And you can kinda see in these pictures how just the visual in the first year of how, I mean, he almost didn't look like who he looked like before.
That was tough to take as a parent, you know, because all of this was from a brain tumor, and when they told me he had a brain tumor, I thought that was the worst thing anyone could tell me, and then here we are. So what is life like with hypothalamic obesity? So this is 8.5 years. He's 13 now, so we've been dealing with this for this long, and we have a lot of fears around him developing obesity-related conditions. So we already have this long list of conditions we're managing every day, two of which could be fatal. So we're constantly managing levels and assessing where he is to keep him safe. But we then have fears that he could develop obesity-related issues on top of these, like sleep apnea, hypertension, diabetes, and fatty liver disease.
A couple of years ago, suffered from aspiration pneumonia because he was eating so fast and so much at once that bits of food were getting into his lungs. He eats so fast and so much at one time that we're constantly worried he's gonna choke. He has a tree nut allergy, so that adds another layer to this because we have to watch him at all times. Because Alex is very clever, and if we're at a social event, and he sees some lovely, unsuspecting grandmother type, he goes right to that person and asks for food. And then you don't know, oh, well, does that brownie have nuts in it? So we're constantly watching him. He food seeks at night. Just the other night, I heard a noise at the garage door.
He was up at 3:00 A.M. in the garage. We have food locked up in the garage, trying to get through the lock. So, you know, I sleep with one eye open, always. And you can see we lock all of our food up, our refrigerator. It's a constant stress on our family. We're socially isolated. It's the holidays. This is our least favorite time of the year because we're always worried about family gatherings and events. And it puts a lot of pressure on our, not just our immediate family, but all of our family, because everyone worries about having the food out too long. What's on the table? Where's Alex? If you're in an event, he'll disappear with food in his pockets and hide in the bathroom... And he also has orthopedic issues.
So immediately after, when he started gaining the weight, he started having a lot of trouble with his legs and feet and walking. So it's kind of one of these other side conditions a lot of these patients face that isn't often addressed. But the thing that I should say is that we manage his, we manage his care so closely, and we manage his diet so closely. We lock everything up, and then we take painstaking efforts to keep him safe. But he is on the borderline of overweight and obese. He's 94.6 percentile, and that takes daily effort. He doesn't go to school during mealtimes. He goes to school in the afternoon after lunch, and the other day I get a call that he stole food out of another kid's lunchbox that was in on a shelf.
So that's a lot to think about. So this is Alex at a party. He was watching this pie the whole time, and we were watching him to make sure he didn't get in it. And I think that kind of shows you a little bit of how he's preoccupied around food all the time. Imagine somebody, I mean, you have kids, and kids ask you a lot of questions, but this is Alex: "Mom, it's 46 minutes to lunch. Mom, it's 11:20 A.M., lunch is at 12:00 P.M. Mom, it's, you know, 15 minutes to lunch." He is watching that clock every minute till it's lunchtime. So what if there was a treatment for HO? Oh, I have a slide. I'll go back to that. What if there was a treatment for HO? You know, what ... Would Alex be able to think about other things?
Like, he, his mind is so occupied by food, and he's a smart kid. You know, I, I feel like his learning would be better if he wasn't thinking about food all the time. Just the things that he could do if that wasn't always what he was thinking about. You know, could eating meals be an enjoyable family experience? Because right now, we, when we eat together, we're trying to keep him from putting too much food in his mouth, and that is all we do during meals. "Alex, take smaller bites. Alex, don't put so much food in your mouth." Would he be able to make friends? Because right now, he doesn't have friends. He's not able to make friends. He can't go over to someone's house because of the food situation. He, all he talks about is food.
You know, it's so all-consuming that there isn't space in his life for friends. And would he be able to have some independence? I mean, what if in the future, he could possibly get a job because he wouldn't be inclined to steal food from his coworkers? So these are the things that I think are, you know, quite possible now that we have a potential treatment. And I wanna go back to this. So the Raymond A. Wood Foundation, we published a caregiver burden study in August. And so we surveyed caregivers on the impact of disease around craniopharyngioma. And we found that in the survey, the data showed that about 80% of the patients had weight problems, and that hyperphagia or insatiable, insatiable hunger was about 50% of those patients. So it's a, it's, you know, manifests in different ways.
But 80% of caregivers are at risk of depression, and I can vouch for that. You know, it's really challenging to manage this all the time and to deal with all of the social implications and the guilt. And so, you know, obviously, that is a mental load that we carry. And these are some of the quotes that we have had over the years from patient families, and I think it's, you know, important to kind of call out that the initial weight gain really quickly after surgery is, that is scary because you don't know what's happening. And then you're on this 1-2-pound weight gain on average, weekly after surgery.
So you're watching this person literally double in size in front of you, and no matter what you do, all of your attempts to thwart that weight gain tend to, you know, not be successful. And it is really about fear, isolation, and hopelessness. And a lot of our kids put themselves in harm's way or others to get to food. Siblings suffer a lot because of this condition. And, you know, just from an adult perspective, doubling in size after tumor surgery without understanding what's happening to you is... That's a tough thing to manage.
So, you know, with setmelanotide, where our patient community and myself as a caregiver are feeling very hopeful, this is, this is a huge thing for us, and, you know, we are so glad that something is out there that can potentially help our kids and our family members and our loved ones in the future. Thank you.
Q&A. All right. So we'll, we'll get started with some questions from the audience, and then we'll also invite you guys. But first, I just want to say thank you. Try to describe it.
... Okay. I think everybody heard that, but, but anyway, thank you, and of course, Dr. Miller, and you said just about a lot of your career to trying to figure out how to help these patients. So, Corinne?
Thanks. I think on one of the slides, it referenced like 59% of patients are on metformin or another kind of therapy for the obesity function, like part of their HO. I guess, why would patients not be on therapy? And do you expect there to be any change in terms of impulse to treat with the advent of IMCIVREE in this population?
Yes, I think that people will be much more prone to treat, you know, with this drug once it gets approved, you know, and so. But the reason people are not on metformin therapy, it doesn't work. You know, so some parents will continue their kid on metformin just because, it, they feel like they're doing something, but the great majority do stop it after a while because they realize that it's not doing much of anything. It's the same with stimulants. We see some people on stimulants for long periods of time, even though they're not actively losing weight on the stimulants or having good appetite control on the stimulants, but it makes the parents feel like they're doing something proactive. Right? Is that a fair statement? Yeah. Okay. So yeah, so that's why. So the, those numbers are because people stop treatment.
Cool. Yeah.
Oh, sorry. Hi.
Oh, sorry. Yeah. Hey.
Whitney from Canaccord. So on the stimulants and also GLP and GLP-GIP, I think you mentioned, you just kind of spoke to the lack of durability of the weight loss or lack of continued weight loss. So actually, can you clarify, is it lack of durability of weight loss that's seen?
Correct.
Or... Okay.
Mm-hmm.
And then what is the time course of that, I guess? And can you compare and contrast?
Typically, about a year.
A year. Okay.
Mm-hmm.
I guess, can you talk about your experience with setmelanotide, I guess, for the patients you've had beyond the year?
Yeah. So, so far on the 2 patients or on the... How many patients do we have left? 3. Or, on all three that are still on setmelanotide, all of them have continued with excellent weight control. As Dr. Meeker mentioned, one of the, the kid that he mentioned that has had a regain in weight is because he's an adolescent young man who is also, you know, on testosterone and growth hormone, and his weight was so-- had gone so low on setmelanotide that I was like, "Eh!" You know, we need- we actually want him to, to stabilize, you know, and, and he did, but then when we had to add testosterone, you know, of course, his appetite went back up again and whatever.
Still very much better controlled, 1000%, his parents would say, than pre-drug, you know, 'cause he's not talking about food all the time, he's not asking about food all the time, he's not stealing food. But the weight itself, as Dave mentioned, is not necessarily the end all be all for these patients, you know, it's quality of life. And so but, but regardless, except for him, everybody has continued down, over the course of almost two years at this point.
Hi, thanks for a very interesting presentation from both of you. Phil Nadeau from Cowen. I just wanted to dive a little bit more deeply into your last point in terms of BMI reduction, weight reduction versus hyperphagia. What really contributes to the improvement in quality of life for patients on setmelanotide? How much is it, the reduction in hyperphagia versus the reduction in weight? And can you... I'd love to hear from, from both of you, like, what, what would be clinically meaningful? And then also, in terms of the magnitude of reduction, what is clinically meaningful? Clearly, if you get a patient to, to normal in either of those categories, it's, it's very meaningful. But, like, how much of a reduction in hyperphagia and BMI would patients and caregivers appreciate? Thanks.
Any, is the answer to your final question, correct? Any, any reduction in these things is helpful and clinically meaningful to families. In terms of the quality of life, I think it's a combo of both weight and hyperphagia. I also have personally said to Rhythm for many, many years that I actually think setmelanotide does have an effect of reducing psychiatric issues like depression and anxiety. I see it. I mean, we always worry about anything that works in the brain, possibly increasing your risk of depression and anxiety. And in this population, you see exactly the opposite. They become more active, they're just happier. All the parents say it. The kids got a smile on their face all the time now. They have more energy, they're not taking a nap after school every day, you know.
So it's all of those things combined. And I'm sure that part of that is the weight, right? Because if you don't have the weight, you know, the weight's coming off, your sleep apnea gets better, you sleep better during the night. You don't have the hyperphagia, you're not getting up at night to steal food, so, you know, you feel better. And so I think it's really a combination of different things, but I do honestly believe that there is some actual possible changes in sort of overall mental health in a very positive way.
Yeah, and just to add to that, in our caregiver burden survey, we found that, you know, there was a really strong correlation with burden to hyperphagia. So while the weight was, you know, an issue for sure, there was even more of a correlation of burden to the hyperphagia. And I will say, you know, in the beginning, and certainly still, I mean, the weight is a big issue to us because we don't want any more medical conditions, and we certainly want them to feel good. And I mean, this, the social stigma is still there, but, you know, for us, too, the hyperphagia is what really keeps us from going out or doing... And, you know, we-- many of us parents and some have this experience, our kids steal, so they can't be left unattended in stores.
So the hyperphagia has a really high impact on quality of life. So, you know, while both are very important, you know, we're working to collect more data around the impact of hyperphagia.
Well, and just to speak to that point, one of the things that every parent in the Phase 2 trial mentioned is they can go to a party now-
Yeah.
and the kid doesn't look immediately at the food. They'll go to the pool with the other kids. You know, it's not all consumed by where the food is and what the food is and when can I eat that food, and what can I eat out of that food that's okay for me, you know, kind of thing, so-
That would be amazing.
I mean, that's life-changing.
... Thanks for hosting the event. I'm Michael Higgins, Ladenburg Thalmann. Just a follow-up from earlier question for Dr. Miller on the patients that you're treating. Have you noticed hyperpigmentation in these patients, and how problematic is that? It seems like they haven't dropped off, but how big of an issue is that for your patients?
It's not an issue at all. So I've been doing studies with Rhythm since the beginning. I was part of the very first trial with setmelanotide, which was for Prader-Willi syndrome, and then part of the genetic obesity stuff, and for those patients, the hyperpigmentation was a much more significant issue. For these patients, they don't care, like, at all. Like, they're, they feel so much better that it's not an issue, like, it just isn't. And so, you know, we see it, it's there, everybody gets darker, you know, but it used to be more, you know, I mean, in the genetic obesity population, specifically, you know, African Americans, Asians really hated it because they didn't want to be darker or have, you know, more dark spots or whatever. And in this trial, we have, you know, all races, and nobody cares.
Like, they're not dropping because of that. That is not an issue at all. So, it's kind of remarkable. And I keep saying that to people, I'm like, "This is really interesting." Like, we've seen people drop off because of this side effect of the drug, but in this population, not at all.
Hey, good morning, Derek from Wells Fargo. Just two questions. First, for Dr. Miller, I guess, is the patient journey that Amy talked about with her son, is that more typical just because it's seen more in children, or do you see adults also kind of with that weight gain, and how is their journey a little bit different, maybe with on diagnosis? And then, just kind of question on kind of comorbidities. You kind of touched on this a little bit, but do the current treatments address any of, like, again, some of the diabetes, maybe you're talking about metformin, and I guess the role of IMCIVREE and addressing that as well? Thanks.
Good question. So, so the answer is craniopharyngioma is most common in children, not in adults. I don't remember what the cutoff is, but adult kids. I am also a pediatric endocrinologist, but, but that being said, I mean, in our current Phase 3 trial with Rhythm, we have many adults, and but they were all diagnosed as children. So I couldn't answer the question about if you were diagnosed as an adult, because I just don't know the answer. Do you know our people?
I can kind of speak to that. So there's two forms of cranio, and papillary craniopharyngioma does affect older adults. So it's a little bit different from the childhood version. We have adults. I have one in particular, who she was diagnosed with the tumor and treated and gained 100 pounds after treatment. And this is a woman that exercised, she ate right, so she didn't know what was happening to her. So she started working out really hard, I mean, hours at the gym, working out. And I was kind of watching her story, and it turned out that she was never told that this was a possibility from her tumor. So she thought it was her, something she was doing wrong, that she was, you know, gaining all of this weight.
When she found out about hypothalamic obesity, she was so, you know, just it totally changed her perspective, and she was like, "now, I know that there's a reason for this." I find the adult population, there's sort of a, they're not as diagnosed as often, and that's probably just because the care is very different from pediatric patients, but it is a challenge for them. And so, you know, and many have had to not take, you know, continue with their jobs, that kind of thing, because there's hyperphagia and issues with that. So hopefully that helps shed light on those.
That's good. Thank you. I did not know that. Pediatrics.
Yeah.
And the answer is that IMCIVREE has reduced all of the comorbidities associated with the obesity. So we see people coming off diabetes meds, we see people coming off blood pressure meds, cholesterol meds. I mean, it's quite remarkable to see the changes. The other thing, like I mentioned before, is we've seen people come off antidepressants on it, which is, right? I mean, it's because this is a really hard condition for these individuals to go through, and especially as they're becoming adults and, you know, with this condition, because they have panhypopituitarism, they also can't have children, right? They're infertile. And so add that burden, you know, as you get into your early twenties and thirties and to everything else you're dealing with. And it is really hard.
I would say a lot of these, most of these patients are on an antidepressant at that age, you know, and so to see them be able to come off and just live a happier life is really remarkable. Mm-hmm.
Hi, good, good morning. Dae Gon from Stifel. A couple of multi-part questions, if I may. Dr. Miller, if we think about the biology of the signal malfunction that is affecting HO patients, and setmelanotide is basically curtailing that or bypassing that issue, I guess, to what extent would you expect some kind of a stabilization or a plateau effect in these patients since you would be maximizing that signal restoration? And related to that, once you restore that, how would you think about administering GLP-1s or GLP-1 GIPs, since you could potentially amplify that? And I think the Obesity Week kind of talked about some of those potentials.
And then second question is, if we go back to one of your commentaries earlier, how the endocrinologists don't necessarily see the weight loss as the primal, primary goal, but rather the hormonal imbalance, what kind of education do you think needs to happen to make sure endocrinologists start thinking about weight loss as a sort of secondary or indirect output of hormonal restoration?
That was very many parts to that question. What was the first part of that question was, Signal restoration, yes. So yes, I expect to see stabilization of that. And, and that is what we're starting to see over time, is stabilization of the BMI and the weight. And so as Dr. Meeker mentioned earlier on, you know, at some point there becomes a set point, right? Where that's just where they are. That may be for that particular individual, it might be a BMI of 32, but certainly he's healthier than at, when his BMI was 52, and he's happier, and he's, you know, not eating as much, you know, and he's not hungry, you know? So, so yeah, there is, there is going to be a stabilization for sure. I have no doubt of that.
And then I don't know the answer to the question about adding the other meds to this, whether or not that would augment, you know, anything or not. I'm really not sure. Because, again, my experience with the GLPs and GIPs are pre this drug, right? I mean, so and just knowing what we saw naturally, you know, with those medicines. And I remember very distinctly, about two years ago, someone said, "Oh, these are miracles for these HO patients!" And I was like: "Just wait. You know, it's not forever." You know, this, I think, is kind of a miracle. I mean, to watch these patients continue to lose weight and then ultimately, like I said, to stabilize.
So yeah, I think there's gonna be some that start out heavier that probably are gonna end up heavier than we would maybe like them to be if we were as doctors, you know, but that might be their set point, and they'd certainly be healthier, even at that set point, because it's lower than what they are without setmelanotide. And then the third question was? Oh, yes, yes, yes. Okay, so this is, this is where Dr. Meeker has made me a fan, is when he said that this is hormonal replacement. No offense. Yeah. I was always a fan. No. Yeah, because I think that's what, that's what we have to emphasize to endocrinologists, right? Yeah. Is that this is not a weight loss drug. This is hormone replacement for something that they are unable to make on their own.
To me, done deal. Would you?
Yeah. I mean, when we were first presented with all of these endocrinopathies that we're dealing with, we were told everything is a replacement, but there are still things that aren't being replaced, obviously. I'm, I'm Alex's living endocrine system. And, but, you know, this is clearly—I mean, clearly, that pathway is disrupted and, you know, replacing that missing element, I mean, the, the possibilities of what that can do is huge and should be expected. And I think you were mentioning the diagnosis of HO, and, you know, I suspect, and this is just a hunch, and I kind of saw it with Alex, is the doctors are a bit afraid to diagnose it because they don't have something to prescribe for it.
Anything that's possibly used off-label right now takes a lot of management and trial and error because there isn't data to support it. So we've tried a lot of different things that, you know, ended up not working because, one, you know, it was just such an effort to try to find the right dose, and even then, it wasn't fully effective. So I think there's a little hesitancy. It's like the elephant in the room, kind of.
For sure. Mm-hmm.
So that's a good place to end. And I think we've highlighted from the earliest point when we got involved here about how this rare disease differed in the sense that these patients, because of the tumor and the surgery, very high rate of diagnosis. I think what we may be learning, and as Amy and Dr. Miller said, the number of patients who have not been given a diagnosis may be higher than we think. And that's certainly true for most rare diseases. And, you know, if you've got a disease for which there is no therapy, as a physician, if you miss the diagnosis, so what? So it's really once there's a therapy and something to do, it doesn't matter what disease it is, it completely changes the overall paradigm.
I think it'll be very interesting to see if, you know, setmelanotide continues to perform and becomes an option for these patients. The whole diagnostic journey these patients are on may also change significantly.
Definitely.
We'll see where that goes. All right, well, we'll end this part of the session. Thanks to both of you. Really great. Have you seen this slide before? No. So, we talked about EMANATE, but I think this is just to remind us that the DAYBREAK, as we're gonna move now to talk about DAYBREAK. We took a tentative step, if you will, down this pathway with these four genes that we're studying in our phase three EMANATE study. But, I'm not going to front-run Dorit and Patrick here. But I think the only thing that I as I get into the study...
The one thing I just ask you to think about a little bit, if you think about clinical trial development, what is the most challenging aspect of clinical development, which is incredibly difficult? And I will argue it's heterogeneity. So if you want to run a perfect experiment, you look to identify a group of patients who look exactly the same, so that your drug intervention is the only variable. I have a bunch of patients, they're all the same, one gets the drug, one doesn't, and so at the end of the day, I can be very confident that if I see a difference, it's probably due to the drug. So why do Phase 2 studies tend to have better results than Phase 3 studies?
Because in Phase 2, we can be really good at identifying that population, and then we go to our big Phase 3s, and suddenly, you have many more sites, and it becomes much more challenging to try to enroll that population that got me my Phase 2 result.... So then you go to a rare disease, and what's the challenge in a rare disease? It is overwhelmingly heterogeneity, because by definition, it's rare. You don't have the luxury of saying, "I want, you know, a bunch of people who are 5 ft 5 and, you know, blue eyes, and whatever," right? I mean, it's, you have to take whoever you can find. Why do we run trials where we enroll patients from the age of four to 65? Because we need the numbers, and the idea that a four-year-old is gonna respond the same as a 65-year-old is zero.
But somehow we need to interpret that data because that's what you're forced to do in a rare disease, is to bring in all of these things. So you're gonna see some data sets here in the DAYBREAK world, which are extremely small. And the journey that we're on, and that Dorit and Patrick are gonna help explain a bit how we're gonna be thinking about this, is how to understand these small data sets and begin to sort some of these variables. A lot of which are in the realm of the genetics, which is, you know, one gene doesn't the same as the next gene kind of thing. And so we'll walk you through that. But I think that's the headline here for the Phase 2 study.
I think really exciting from our standpoint in terms of potential here, but complex and complex for extremely understandable reasons. With that, I will introduce Dorit.
Good morning, everybody. It's a pleasure to be here today to present the top-line stage 1 BMI data from the DAYBREAK study. Folks, I don't know if you've seen this slide yet today. I'm not going to belabor it too much. What you're seeing here, as you know, is the integration of the hunger signals from the agouti-related peptide neurons and the satiety signals from the POMC neurons, which interface with the melanocortin four receptor neuron to control caloric intake, energy output, and generally help with weight maintenance in adults or appropriate weight gain in children. You've already heard earlier about how this process can go awry. In individuals with variants that either reduces the satiety signal or increase the hunger signal, you can get this balance thrown off kilter as well.
So you can see increased hunger, hyperphagia, reduction in energy expenditure, and early-onset weight gain. You're already well aware of our work in individuals with biallelic mutations in PCSK1, POMC, leptin receptor gene, and the genes causing Bardet-Biedl syndrome. David has already mentioned the Phase 3 EMANATE study looking at the effects of setmelanotide in individuals with heterozygous mutations in the leptin receptor, PCSK1, and POMC, as well as in individuals with variants in SRC1 and SH2B1. Not gonna tell you any more about that. More to come in the future. Moving on to the DAYBREAK study, how do we select these genes? We used a validated ClinGen framework, which integrated a number of points that you see listed on the slide here. Looking...
To select a group of genes which were in the melanocortin four receptor pathway, which were linked with obesity, and which we thought had a strong or very strong probability of responding to setmelanotide. You're gonna see a bit today about whether or not we did a good job in selecting those genes. This is a cohort of 31 genes, which were initially selected for inclusion in the DAYBREAK study. Now, as is common in Phase 2 studies, we ended up closing a few cohorts early due to either lack of interesting signal or difficulty with recruitment. So in the end, we included 24 genes in the final study cohort, and the ones who were crossed out were the ones that we closed early. On this slide, you see the design of the DAYBREAK study.
Individuals meeting the criteria for enrollment, so eligible variants in one of the genes I showed in the last slide, the proper age range and having obesity, were then enrolled in the study and in the open-label stage 1, where everybody got setmelanotide for 16 weeks, including two weeks of a dose ramp-up. Those who completed stage 1 were then analyzed to see did they meet the primary endpoint of weight loss, and those who had the met the pre-specified endpoint for weight loss were then randomized into stage 2 of treatment with setmelanotide versus placebo. This is our randomized, double-blind, placebo-controlled portion of the study. That is still ongoing. More to come on that in a few months.
Today, I'm going to present the stage 1 data with looking at our primary endpoint, which is what proportion of patients by gene cohort achieved a reduction in BMI of at least 5% from baseline. On this slide, you see the demographics of our study participants. There were 164 participants in our full analysis set. And as you can see, we had 109 adults, 55 children, and these participants were, by design, quite obese, so average BMI of 48.5 in the adult participants, ranging from 40 to up to 74. For the children, the average BMI Z-score was 2.6, and as David already mentioned earlier, a normal BMI Z-score for children is between -2 and +2 standard deviations around the mean for age and sex.
So as you can see here, our disposition slide. So as I mentioned, 164 participants enrolled in the study and received at least one dose of study drug. Of these, 52 participants discontinued prior to the end of stage 1. 100 participants fully completed stage one, and an additional 12 discontinued but had their end of study visit within a pre-specified two weeks of the end of stage 1, so were included in the week 16 completers analysis. Of those 100 patients who completed stage 1 fully, 49 patients met the endpoint for of weight loss for inclusion into stage two and then were randomized. We don't have time today for me to review the results of 24 gene cohorts, so we picked six of these, which had some interesting results to review.
What you can see on this slide is the proportion of patients with these various variants in either these genes or gene families who responded to setmelanotide, ranging from 25% in individuals with SIM1 variants, 56% in individuals with PHIP variants. This box and whisker plot is a little complex, but what it's meant to show is the variability of the response along with the average response. So the average reduction in BMI in each of these genes or gene cohorts, which was around 5%, ranging from 4%-6.5% reduction from baseline. So just orient you on the Y-axis, you see percent BMI change from baseline, with zero being the baseline, and then you got a red line at the -5%. So 5% reduction in BMI, because again, that was our primary endpoint.
That said, as David mentioned earlier, there is a lot of heterogeneity here. Individuals do not necessarily have the same variant. In any given gene, there are multiple different variants, and Patrick will get into that more a little bit later, so I'm not going to steal his thunder. But because of that, it's actually really important to look at individual-level data because that tells a very interesting story. So for the next few slides, I'm going to break down each of these different genes or gene families and show you the results of the level of individuals on waterfall plots. As you can see here, it's a similar orientation to what you saw before. On the Y-axis, you see percent BMI change from baseline, with zero being where they had started out. And each of these bars represents an individual.
This is, again, the red line at -5, because that's 5% reduction in BMI from baseline, the primary endpoint for the DAYBREAK study. So for individuals with the SIM1 gene, you can see that, 5 out of the 20 individuals who entered the study and the 16 individuals who completed stage 1, met the primary endpoint for BMI reduction with quite a bit of variability, right? So 1 individual actually gained weight, and a few individuals lost a substantial amount of weight. And there's some reason about to discuss that some more. And again, I'm going to let Patrick talk about the variants. This is in individuals with variants in the MAGEL2 gene. And here we had 10 patients start, 7 patients complete, and you can see 3 patients met the primary endpoint for BMI reduction.
TBX3, small cohort, but an interesting signal. We had 5 enter the study, 3 completed stage 1, and of those, 2 responded to setmelanotide. The next couple of slides are group of gene families as opposed to individual genes. They have homologous functions, so we looked at them together. You can see here on the bottom right a waterfall population for each individual gene. So this is the Plexin A group, and what you can see here is, again, substantial variability in the response. So 12 out of the 40 who started, so 30%, and 12 out of the completed responded to setmelanotide, and then a few more were almost there, not quite.
But what you might notice is that the Y-axis here looks a little bit different because we had one person lose 23.6% of BMI from the reduction in baseline. So again, quite the individual level variability. This is the SEMA3 cohort. Again, you've got the legend over here. And this cohort showed a more consistent response, I would say, albeit with, again, ongoing variability. But a high proportion of those who started, especially those who completed stage one, responded to setmelanotide. I'm so sorry, can you not hear me in the back? I apologize. I apologize for that. I'll try to speak to the mic going forward. And finally, we move to the PHIP gene, which this was the gene for which people showed the most consistent response to setmelanotide.
9 out of the 16 patients who entered the study and almost 70% of those who completed the study responded to setmelanotide. And that does make sense, thinking about the biology. So PHIP influences the transcription of the POMC gene, and variants in PHIP associated with obesity have reduction in transcription of POMC, so reduced production of alpha-MSH. So it makes sense that the setmelanotide would treat this pretty effectively. That's all I really have to say on the clinical results of the BMI loss, and I will now turn it over to Patrick to discuss the genetics behind the DAYBREAK gene. Thank you very much.
Great. Thank you so much, Dorit, for your introduction. Yeah, nicely summarizing the results of the Phase 1 trial, the stage 1 of the trial. So as Dorit mentioned, you know, there were six interesting signals from six genes. I don't necessarily have the time to go through all six today in depth, so what I'm gonna present here is a secondary analysis, looking at some of the variants in three of the genes as an example. So we're gonna look at, I mean, you're familiar with this figure, but I'm gonna look at TBX3, which is on the POMC side. It's actually a gene that's required for the differentiation of the POMC neurons. We'll also look at SIM1 and the MC4R neurons, again, required for the differentiation of those genes.
And then, we'll look at one of the SEMA3 family genes, SEMA3G, which actually directs the projections, neuronal projections from POMC to the MC4R. So it's an intermediate, intermediary gene. So, just to lay the sort of groundwork for variants, you know, we're talking about rare variants here, but collectively, rare variants are actually quite common. And you really get a view for that when you start to look at you know, the hundreds of thousands of genomes and exome sequences and databases like the gnomAD. So for example, SEMA3G, that gene has 1,200 rare missense reported in gnomAD. So that basically accounts for 50% of all of the coding bases have a mutation in at least one individual. And clearly, not all of those are disease-associated.
So to help clinical labs, you know, really interpret these, the American College of Medical Genetics and Genomics, ACMG, developed an evidence framework, to apply to rare variants. And that will lead to a categorization of the variants in five different categories. So they correspond to here on the right-hand side of this bell curve to pathogenic variants. Those have a 99% probability that they're truly causal of the disease. One step down from that are your likely pathogenics. Those variants correspond to a 90% probability that they're causal of the disease. Mirrored on the left-hand side of the curve, you have benigns and likely benigns, where we have, again, importantly, very good information that these variants are not causal of disease.
Now, in between those two, there is a very large fraction of variants, where we simply don't have any evidence either way to classify them as benign or as pathogenic, and collectively, those are called variants of uncertain significance. Now, what we do know from past studies is that, looking at VUS variants, 20% of those are likely to be reclassified up towards pathogenic, and 80% of those are likely to be reclassified down towards benign. Now, in terms of the trial, variants were included if they were VUS or above. So we're including a number of variants that, you know, we know are likely to be benign.
But given the number of the VUSs and, you know, the fact that 20% of those are likely to be pathogenic, we had to include them in the trial. Okay, so a number of retrospective studies have now been carried out, and the largest of which was, you know, just recently reported at ASHG by Invitae. They're looking at 1.8 million variants now. So these are 1.8 million VUS variants, and they're seeing, you know, looking at the trajectory of how they've been reclassified. And again, a number of studies have been reported, but the important point is that they're all coalescing around that 80-20 split, so it's becoming fairly well established. And the sorts of data sources that they're using to reclassify those variants, so it's a mixed bag.
Some of it is new tools like prediction algorithms, SpliceAI. There's a couple of newer AI tools that have just been released, like AlphaMissense and PrimateAI 3D from Illumina. So this is just gonna accelerate going forward. There's classical genetics approaches, like testing family members, but by far and large, you know, the largest fraction of data sources is new data. So looking at, you know, things like allele frequencies and databases like the gnomAD and functional data, you know, whether they're in vitro assays, whether they're multiplex or not. And just a point on functional assays, you know, the first three categories that I listed, they're largely passive to a company like Rhythm. You know, it's community-generated data.
But for functional data, that's an area where we can be proactive, where we can generate data internally on our genes of interest. And, you know, the sorts of assays that I'm talking about here, they're in vitro assays, where you take a gene construct, you introduce a mutation, and, you know, you transfect those into cells and then, carry out some sort of an assay comparing wild type to those specific mutation carriers. So we're not looking really necessarily at animal models and in vivo systems here. But, you know, they're very useful for the classification of variants. So as an example, we did a comprehensive look at PCSK1, POMC, and LEPR and published a paper on all missense variants in those three genes at the start of the year.
And since then, one of our partner labs, our clinical testing lab, Prevention Genetics, has been able to reclassify 90 VUS variants in those three genes using our data. Okay, so let's get into one of our first examples. This is the SEMA3G. So this happened that, you know, since trial enrollment until data readout, five individuals with four unique variants were reclassified by PG from their starting classification as either a VUS or likely pathogenic to likely benign. And four and those account for four of the six non-responders. So the responders are in the top portion of the table with the, you know, the response is actually in the third column. The black line delineates the two. I've put arrows for the reclassified variants.
You can see that four of the six non-responders were actually shown to have likely benign variants. So overall, if you look at the starting ACMG classifications, your response rate is 57%. When you look at it using the reclassified VUS, when you look at the response rate, looking at the reclassified variants, so we remove the likely benign variants, you increase the response rate to 78%, with seven of nine responders. So our second example is SIM1. So this is one step back from ACMG classifications. This is an example where Rhythm and, you know, there's a couple of other published studies have generated some in vitro data looking at SIM1 variants.
SIM1 itself is a transcription factor, and so the in vitro assay essentially is assaying its ability to induce gene expression. So the in vitro assay, essentially, you co-transfect SIM1 construct, be it wild type or with your specific mutations, with ARNT and HRE luciferase into cell lines. You wait a couple of days. So the wild type SIM1 is able to initiate the luciferase, which releases light, so that gives us a baseline for the wild type. And then we can repeat that experiment with different mutations and see the level of light that's produced by the different mutants, and that gives us a gauge of how they're affecting the protein function.
So at the time of the experiment that was carried out in-house, Rhythm had identified 213 different SIM1 missense through its different sequencing programs. And the way this slide is laid out, there's a schematic of the gene in the center of the slide. Then each of the dots is one of the missense. The missense are arranged on the X-axis by position and on the Y-axis by their percent activity compared to wild type. So all of the missense that are plotted above the gene, those all showed they retained over 70% activity, and so they're classed as wild type. They had no effect, essentially, on the protein.
The ones that are plotted below, the gene figure, those all showed a reduction in activity and were classed as either moderate or complete loss of function. So when we look at our complete analysis, and again, here I've included the percent BMI change from baseline in column 2, and then the results of the functional assays are included in the final two columns. So the second to last column shows any results from published studies, and the final column is the result of the Rhythm assay. And where we had results for both, they were concordant in 100% of cases. So highlighted in the dark blue at the top of the table are the responders.
For those, you can see that we had four out of five variants assayed, and 100% of those showed loss of function. Then for the non-responders in the light blue, we had 9 of 11 variants assayed, and 56% of those showed wild type activity, so we wouldn't expect those to have a deficit. So in a secondary analysis, if we exclude those wild type variants from the SIM1 response rate, it increases from 31% to 45%. I also want to highlight one other observation here. So two of the four loss of function variants in the non-responder group were actually the same missense, the 717 histidine. And in fact, we have three carriers of that 717 histidine in this dataset.
One was a really good responder, one with moderate response, and one with no response at all. And actually, we can explain this pattern. In the very first paper that was reported by the Farooqi group, they actually called out this variant and showed that although it was moderately damaging, it is actually it expressed... It's variably penetrant, so it doesn't express in all carriers. Our third example is TBX3. So here we're one step behind again. So this is another of the... This gene is also a transcription factor, but in this case, we don't have functional data. But what we do know is that the structure of the gene is highly informative.
So missense that have been reported, they all localize pretty much to the T-Box domain. That's a very highly conserved region of the gene that's involved in the DNA binding. And if we look at our responders, both of those, and I've highlighted them on the slide by the red arrows, both of them, they localize inside of the T-Box, inside of this domain. So we have one that's basically in the middle of the domain and one at the very first residue. And we would expect these to have a much more significant impact on the gene function than the three other missense in the trial that were all outside of the T-Box.
Okay, so, you know, to sum up, if we in the secondary analysis, if we just take the ACMG reclassifications into account, we have a big impact on the SEMA3 family. So for the family of genes overall, that's SEMA3A through to G, the response rate increases by 11%, from 61% to 72%. As I presented earlier, if we look at SEMA3G alone, that gene had an increase of 20%. And then if we add in the functional data from the other two genes, that increases our response rate for the trial overall, by 5%, up to 48.5%.
So many of these genes, you know, although many of these genes don't have good prevalence estimates in the literature, so we've provided some here based off of our URO program. So these are projections from the URO program sequencing data. And just to note that although the PHIP and TBX3 are relatively modest numbers, these both have syndromic presentations, so they should be easier to identify these patients, you know, similarly to the BBS population. And so, you know, to sum up, even though we don't have, you know, huge numbers here, we're looking at small numbers. We're seeing a very clear correlation between the function of variants and their response rates.
and so, you know, as we deepen our understanding of our candidate genes, we would hope to be, you know, better identifying our responders, our responder population. So thank you for that.
Thanks, Patrick. So, now we'll move on to our next generation program.
Good morning, everyone.
You have to press mute.
Oh, sorry. Good morning, everyone. I have a great pleasure today to introduce a new selective MC4 agonist, next generation of setmelanotide RM-718. This molecule was built here in Rhythm, and it's designed to be more MC4 specific with high potency. At the same time, we designed to eliminate activity towards MC1 receptor, and therefore possibility to eliminate hyperpigmentation effect seen with setmelanotide in patient. Also, we designed it to be patient-friendly as a weekly formulation for patients. All this extends the patent protection for around 10 years when we compare to setmelanotide up to 2041. It is important to say that 718 was built first picked from the library of compounds which were made out of the chemical space of setmelanotide.
Same as setmelanotide, RM-718 is a cyclic amino acid peptide, but it's shorter for one amino acid. Setmelanotide is 8, octamer, 8 amino acid peptide. As I said, it's designed to be very MC4 specific, that it's also MC1 sparing, and for patient, we give them as a once-weekly injection, which is sustained release formulation. Today, I don't have time to tell you all this preclinical development, which led us to hopefully Phase 1 study in the next year, early next year. But I thought I will show you some of the important studies which are showing selectivity, specificity, and safety of RM-718. Initially, we tested the efficacy of RM-718 in the animal model, where obesity was induced in the diet.
These are the rat DIO models, and we designed a parallel study of three groups, where the same dose of setmelanotide daily formulation was compared to the RM-718 daily formulation. The dose was 0.5 mg per kg. As a vehicle control, we had a group of animals which were which were used in the study. As you can see clearly on the graph on the left-hand side, the body weight in the treated animals was reduced significantly from the vehicle control, and the maximal reduction was seen pretty much at the end of the two-week study, and it was around 8% and 9% in set group and RM-718 group, respectively. I want to point out that the reduction in body weight from control was seen pretty much from initiation of a therapy from day 2 of the study.
On the right graph, shown is a cumulative food intake in these animals, and you can see in both treatment groups, in both set and RM-718, the cumulative accumulation of food is lower versus placebo, around 20%. And again, this effect in food reduction was seen from day 2 of the study. Furthermore, we wanted to test once-weekly formulation of RM-718 and compare with the weekly formulation used for setmelanotide these days in a clinical trial. For that study, we used obese Zucker rat model, which is leptin receptor deficient, and so these animals are actually developing obesity and have pre-diabetic stage. One of the very important characteristic of these animals is that they have uncontrolled food intake, so they are hyperphagic, similar to our patient.
Study was designed as a three-week parallel study of four arms. Each group has eight animals, and we compared the same doses of setmelanotide again, and RM-718. The dose was 5 mg per kg to placebo arm, which was our control group. We also in the study introduced RM-718 group, which was those with 10 mg per kg, so the higher dose. We wanted to see some dose effect in the study. And again, if you look at the left graph, body weight reduction was significant from placebo. It reached maximum at the three weeks of treatment and was very similar between set and RM-718 group, with around 13% and 14%.
While in the group of animals, those with the high dose of RM-718, we see some trend increase in body weight reduction, around 16%. One thing I want to point here is if you look at the right graph on the right-hand side, the body weight gain was significantly reduced in those animals. While placebo group was gaining around 70 g during three-week period, overall, in all treatment arms, we see reduction in body weight between 20% and 30%. And you can see that this reduction was the highest within the first week, and then animals maintained the weight. And that's why we see this very flat body weight change from placebo on the right-hand side graph.
In the study, we also measured the concentration of RM-718 in both plasma and cerebrospinal fluid, and you see that based on the dose, we see the increase in concentration in both plasma and CSF, which was also reflected in body weight reduction, which was 13% in 5 mg per kg dose and 16% in 10 mg per dose. As I said to you, these animals have uncontrolled food intake, and they eat usually 35 g, 30g, around 35 g per day, as shown by placebo with the wide graph. What is important in this study is that not only that food intake was significantly reduced, but it was reduced to the levels normal in normal, healthy animals.
So, I'm trying to address this, that hyperphagia was reduced to the extent that animals were eating healthy amount of food per day, which is very important, and accordingly, the water intake was normalized. We also look at fat composition in these animals. Body fat composition was significantly reduced, as well as insulin resistance. But one of very important studies, which was done very early on in the RM-718 development, was to address cardiovascular safety. We know that one of the main features and why setmelanotide is successful as MC4R agonist is that it has also cardiovascular safety, which is very important characteristic. Previously developed compound all had some negative effect, especially to blood pressure and heart rate.
So we did a study in monkeys, non-human primates, which is a species used to actually test MC4 agonist, and be able to see if any negative cardiovascular events will happen. And I know it's a busy slide, but if you look only at the graphs on the now upper right-hand side, you can see results with the observation with RM-718. In this study, where animals were infused for three days with a dose up to 5 mg, 1 mg and 5 mg, during this three-day period, we don't see in the actually RM-718-treated animals, any changes in systolic or diastolic blood pressure, when compared to reference treatment animals, which were those with saline. So you should look at the purple triangle versus green or red line.
This is opposite to Lilly compound, which was used in this clinical trial as a positive control. You can see in both systolic and diastolic graphs on the left-hand side, change from a reference control, which is again shown by purple bar. Animals dosed with 1 mg per kg dose show increase in systolic and diastolic blood pressure shown by those red lines. For those who are interested to see more about the detailed data and changes with Lilly compound, is shown on the table below in the right-hand corner. One thing I want to point here, that animals dosed with RM-718 got a dose of 5 mg. The high dose was 5 mg per kg, around 5 times higher than the dose of a Lilly compound.
You can see that the concentration was around 1,600 nanograms per mL. Very high concentration comparing to 300 nanograms per mL, which was the concentration seen after 72 hours in the animals treated with a Lilly compound. So to confirm cardiovascular safety with the present formulation, we recently finished a study using RM-718 weekly formulation with the doses up to 30 mg per kg. And again, we confirmed this cardiovascular safety, which give us a very nice safety margin of 30x from the planned dose in the phase 1 clinical trial. And this brings me to our next step. So pretty much, we were able in the last year to generate very nice safety and efficacy package, which opened the path to do the clinical trial next year, early in 2024.
The study is designed as a three-part Phase 1 study to evaluate safety, tolerability, and PK of weekly formulation RM-718. Part A is a single-dose ascending study, where doses between 3 mg-50 mg will be tested in patients. These are the doses per day - per week, sorry, and safety follow-up will be 10-14 days. After the interim analysis, healthy obese patients will be enrolled in the MAD part of the study, which is multiple dose ascending study between 3 mg-40 mg, with safety follow-up up to 28 days. And finally, part C study will be MAD type of study in patients with hypothalamic obesity, which is kind of signal-seeking study, where doses between 10 mg-40 mg will be tested up to... And safety follow-up will be 28 days.
Study is designed to have open label expansion later on. So, so far, I demonstrate that RM-718 had similar or improved safety, tolerability, and potential efficacy comparing to setmelanotide. In those vials here, you can see that it shows and appears as a liquid, a light yellow solution, easy to be injected in patients. I told you that RM-718 is designed to be more selective MC4R agonist. In vivo safety results support no off-target cardiovascular effects, which is very important. And we also demonstrated in toxicology study, in 28-day toxicology studies, that we don't see any systemic toxicity, which is also important.
No hyperpigmentation was observed in vivo, and in vivo result in animal models are suggesting potential efficacy for body weight reduction, food reduction, and especially hyperphagia reduction, which is one of the problem in our patient. And altogether, opens a path for treatment in hypothalamic obesity patient. Thank you.
Thanks, Danica. So, last section here, the pediatric results. So genetic diseases, by definition, they're present at birth. As with most genetic diseases, if you could intervene earlier, that would make sense, i.e., potentially at birth, and avoid a lot of the subsequent comorbidities. Challenging, because, again, without good, strong newborn screening, that tends not to happen. It's very difficult to get on that newborn screening list and a long set of criteria. So, these patients, as you've heard, in all the realms we work in, they are on this diagnostic journey. Honestly, if you will, trying to get a diagnosis.
A number of them do get diagnosed early, and they get diagnosed early because it's so clear that something is wrong, presenting with this uncontrolled desire to eat and being overweight for age. And I think, you know, one of the questions that came up about the adults and the peds, I was thinking, you know, the advantage of pediatrics is that the pediatrician is taught, focused on where they are relative to their growth chart. Whereas as an adult, we're all sort of grouped in this world of you're just overweight and, you know, again, diet and exercise. But we don't get the same scrutiny we do as a child, where people were much more concerned about if you move off of that growth chart.
So where we are, you know, I'll show you a little bit of our testing samples in terms of the frequency of a positive result in patients at a very young age, and we are moving forward. We filed our regulatory submission, Type II variation has been submitted to the EMA, sorry, and we'll be filing a U.S. FDA submission in first half of 2024. So with regard to the testing results, so here's POMC, leptin receptor results. Here's the Bardet-Biedl results, and this is by age. So between the ages of zero and two, let's just focus on the PPL line here first. About a 1% hit rate as compared to 0.05%-0.1% as we go through the other ages.
The same is for BBS, where we have a 1.65% for biallelic BBS positivity here as compared to about a 0.5%-0.8% response in the other age groups. And the reason for that is we have many fewer samples submitted at this age group, again, because parents, physicians don't often you know, recognize and are thinking about it. But if they do, the history is much more reliable. And so the presentation that would drive somebody to doing genetic testing here significantly increases the probability that you're gonna have a positive result for genetics with these two genetic tests. But it, this, this observation extends across all of the genes that we're, we're testing here. So it's just a much more reliable history leading to a higher hit rate.
So for the trial, we had a small trial, 12 patients enrolled. Demographics are here. There were seven in the POMC leptin receptor deficiency group, five in the BBS group. Again, the striking thing, these are BMIs, right? So BMI, not great in children to fully assess, but already a BMI of 34 in these children, ages two to six. The mean age, is mean age up there? No, it's mean age was around three. And for BBS, not as severe as this group, but severe with 23. And the better metric of that severity is for these POMC leptin receptor patients, their standard deviation, deviation score, BMI Z-score, was 10.7. And for BBS, which looks modest compared to this, but it was 4.2, which is, again, severe. So, strikingly compromised already at a young age.
Here are the results. So, as you probably saw from the press release, the primary endpoint was this 0.2% or, sorry, 0.2 change in BMI Z-score, clinically significant, but that's not gonna make a big dent in a child whose BMI Z-score is 10 at baseline. So as you can see, over time, the BMI Z-scores trended down, and the change in BMI here, the mean percent change from baseline, despite the fact that these kids are growing, was -18%. So again, quite strong. But as always, waterfall plots, individual patient stories, I think, are where you really begin to understand the data. And so if you look at the POMC group here, which are these 3 patients were POMC biallelic patients.
This is the decrease in their BMI Z-scores. Remember, they had an average of around 10, so, you know, a -7, a -5.5, a -4+, and a minus-- I'm sorry, that's the, the leptin receptor patient there. So again, really striking reductions from very, very severe baselines over the course of a 1-year period. In the leptin receptor, we had this one patient who was, again, extremely severely affected. I'm forgetting exactly, apologies, what his, his baseline BMI Z-score, but he was one of these in the 10 range. I think, frankly, what happened was he dropped out of the trial at seven weeks. You had to start the trial at a dose of 0.05. And given his weight, and I just don't think...
You have to titrate up. I don't think we got to a high enough weight for them to be able to appreciate a difference, and got discouraged and left the trial and was lost to follow up. The other patients, again, for the leptin receptor, which sometimes I think may be more challenging than POMC, but as you can see, these two patients, very, very strong results, very similar to what we saw here. This patient, that's the four patients there. This patient, you know, more modest with -2, but still, 0.2 was our goal, -2 was the result for that patient. And then the BBS group here, ranging from, you know, in the -1 range up to a -3 range.
This one patient, which I'm gonna show you a little more detail, is the only—these were the two non-responders, so this patient was last follow-up at 7 weeks. Then this patient who initially had a response, who seemed to be on a good trajectory and then lost it. I'll take you through what happened there, and then you can see the mean results here and the difference for the two different cohorts. So this is the patient who did have a good response. So started at a dose of 0.5, with a decrease of their BMI. Sorry, BMI is in red and their BMI Z-score is the blue. Had a side effect, which was unrelated to the drug. Nevertheless, the dose was reduced to 0.25.
I think the parents were anxious and the patient began to regain weight over the course of the balance of the trial, even though when they were seen for the follow-up and recognized that they had lost their trajectory and were now regaining, they were dose increased to 0.5. But we had their PK data, and as you can see, early on, I think they were taking the drug, and we had measurable levels, and then we had this period. These are post-dose administration late in the trial, but I think we had this long period of time where they just weren't getting the drug. So again, there's a consistency to the results here, which has been pretty much true, certainly very true for HO, but, you know, obviously, like anything, if you don't take the drug, it doesn't work.
But you know, as a rule, if you are taking the drug, you should see some effect, assuming, and I think this is a question we still, you know, as we get in these different populations, understanding dosing and, you know, the right dose. So this was our standard dosing for our approved label with patients 6 and above, is you start at, you know, one basically and dose escalate to three. In this world, because of the younger kids, we did start at 0.5, and dose escalated to two. Now, we'll be seeking a label... That's on the next. Oh, sorry, let me just finish on the hyperpigmentation. Sorry, on the side effects, which had hyperpigmentation, which is a universal effect.
It's 100% of the patients will have some darkening, for some, they find it bothersome, or the physician scores it. So that's why you don't get 100% scoring on hyperpigmentation, but it's 100% of the patients. And then the others are the injection site and the nausea and the vomiting. So, nausea is hard to measure in these kids, but for sure, they had nausea. The vomiting, again, there was a couple of events that were a little later in the trial related to viral issues and the like, a little more complicated population to evaluate some of this stuff in, but no, very well tolerated overall and very similar to what we had seen in the others.
So our our conclusions here were a very clinically meaningful reductions, as I've highlighted, similar safety profile. And what I was starting to say was that we'll be looking for a label of 0.5-2.5 for this group between the ages of two and six. And then once they get to six, of course, they can go up to three as needed. There's of the 11 patients who are on therapy, 8 are in the bridging program. Three of them have passed the six-year-old, so they're they're now on commercial therapy. I think that is my last slide. So we'll now open up for a few minutes for Q&A, and Patrick. All right, the floor is open, Derek. Okay. Yes.
So the first question came in online from Jeff Hung, analyst at Morgan Stanley. It's just a quick question on the DAYBREAK trial. What were the main reasons for the discontinuations during the stage 1 of the DAYBREAK trial?
There we go. There were a variety of different reasons. The majority are what you would expect: nausea, vomiting, site injection issues, didn't wanna take daily injections anymore, and there are a few who discontinued due to lack of perceived effect as well.
This was an all-comer trial, so back to the, all-comers, meaning you had to have the gene. But, back to Patrick's explanation, there for sure are a significant number of patients that had variants that were probably wild type or benign in that sense, and so not benefiting. And what we've seen across, as with most therapies, right? If you are, not seeing the benefit, and certainly if you're not seeing benefit and you have some early side effects, you know, you're likely to move on. So, I think I'm not surprised at the, the number of quote-unquote, "discontinuations" we saw in this group. Back to my heterogeneous comment, this is just a very mixed group, and yeah. Yeah, Derek.
Hi, Derek from Wells. Just, two quick questions. So first off, just a follow-up on the discontinuations. I mean, do you think, was that expected to see that, that rate of, you know, discontinuation from the trial? And then in terms of the weekly, you know, 718, obviously looking very good, you know, preclinically. I mean, is there still a decision to be made regarding, you know, weekly IMCIVREE versus 718, or have you kind of already decided?
Yeah. So I'll take this. Were we surprised in the discontinuations? No, I, I didn't... The DAYBREAK study was a massive undertaking for a small company. But being a rare disease, we had this 30 genes back to it, just, you know, we didn't know. I, I think what I'm-- we are really pleased about with DAYBREAK is the goal was to begin to sort that list of genes, and it, it, it really did a pretty good job. I mean, if, if we got down to we'll see where we end up. These are preliminary, right? I'll highlight that again. But if we got down to, you know, six or so genes where we felt there's some interest and, you know, the work that Patrick and Dorit are doing to drill down into those six, right?
I mean, next round, we would run it differently. Hopefully, we'd be able to enroll patients that take us to that higher response rate. In other words, by doing a better job on sorting the variants, and that already could make a big difference. So if we can do that, then I think these become quite interesting. So no, I wasn't surprised on that. Then the issue on what to do, what's gonna happen with the weekly? What we've said, and that absolutely hasn't changed, which is our original setmelanotide weekly formulation is on pause. It'll be a backup program. As long as this program looks good, it's clearly a better drug. It has other advantages, as you know. So yeah, we're gonna, we're gonna push ahead.
And hopefully, what you took away from Danica's presentation is, you know, there's limitations to what you can learn in a preclinical space, but these are pretty robust. And so because we're following the path of setmelanotide, I think we can read through to a certain extent that if it looks good here, then hopefully it'll look good there.
Thank you. So, I guess quick call, follow-up on the variant discussion. So it sounds like if you were to move forward with any of those, you would look to further narrow the entry criteria based on the variants. Is that kind of how you're thinking there? And then, second question is what-
Yes, the answer to that was yes, by the way.
Okay. I'll ask one at a time.
Those of you nodding.
Second question is, as you think about setmelanotide versus 718, if you were to move forward there, would you still be thinking about setmelanotide, or is there an option to just gonna move forward with 718 as you think about the next mutations?
Yeah. No, we'll. The setmelanotide, because it's setmelanotide, I mean, we know it works well, and we also know it's not MC1R-sparing. It has hyperpigmentation. So, you know, there's the prolonged half-life, which is more attractive here. I mean, so there's a number of issues where, again, as long as RM-718 moves forward and we'll learn. I think that question will be answered firmly in 2024 as we do this phase 1 study. If it doesn't work, we'll pull setmelanotide off the shelf, and we'll work on it.
This is Corinne Jenkins with Goldman Sachs. One of the things you highlighted there in the pediatric study was the evidence that's really accumulated that you have to stay on drug to continue getting benefit. I guess maybe looking at other hormone replacement therapies broadly in the space, how should we think about a reasonable expectation for duration of treatment, both in these genetic obesity indications as well as HO?
Yeah, we've got a lot of endocrinologists. Actually, Dorit, why don't you take that?
Sure. I'll take that as a pediatric endocrinologist by training. In terms, are you asking about hormonal replacement and hypothalamic obesity for panhypopituitarism? That's lifelong.
Is that a good way to think about duration of-
Yeah.
What's a reasonable expectation for duration of treatment? And maybe that's a good analog.
Okay, I think I see what you're saying. It's replacing a hormone that their body is not making. Either they were never able to make it appropriately due to these genetic variants, or they lost the ability to some degree in the setting of the craniopharyngiomas or other pituitary hypothalamic tumors. So I think if you think of it as like a vitamin replacement, almost, you need it and your body's not making it, that might help set the expectation that it's really expected to be a lifelong therapy.
Okay. And then is there anything else that's required, or can you talk to us about what else is required in order to actually get label expansion down to the two-year-old patient population from here?
So, this trial was agreed upon with both, EMA and FDA. We filed early in, in Europe because, actually the, the expectations there were a little lower in terms of patient number. They just wanted one patient in each of these three different cohorts. So we're well above that. So we have filed on that, and with the FDA, we're just finishing the trial. But no, this is, there's nothing about this package that would, I think, create any concerns in review. So we'll see. But, yeah, I would expect it to be a straightforward label expansion.
Thanks, David. Michael Higgins, Ladenburg Thalmann. Just wanted to follow up on DAYBREAK. We've been talking the last several months about potential market size. What can you share on your work so far? Are there patient support organizations out there, like you had such a home run there with BBS and rare field? Do you have anything like that here? Thanks.
Yeah. I mean, I'll let Patrick comment a little bit on the numbers, then I can also answer qualitatively, yeah.
Yeah. So in terms of the patient organizations, for a couple of the genes like PHIP, there are. It's a syndromic. It's associated with a syndromic presentation, Schaaf-Yang syndrome.
Yeah.
So MAGEL2, so MAGEL2 is associated with Schaaf-Yang. There was a patient organization around that. PHIP is associated with Chung-Jansen syndrome. There's a patient sort of advocacy group around that. So for a few of them, there certainly are. And then there's a number of genes like the plexins and the SEMAs were more similar to the monogenic presentations, like more similar to the PPLs, that would rely on you know, genetic testing to identify those.
I mean, with that characteristic, I mean, the lowest numbers to finish, so 4,000 was on the PHIP. And these are, again, with every rare disease calculation, huge caveats, as we know, and, you know, those numbers move all over the place, as a rule. I think our URO testing gives us some pretty good insight into what the frequency of this gene is and the size of that population. But at 4,000 in syndromic, that's BBS. You know, so is that interesting to us? Absolutely. If the effect is significant, you know, you can do that. You know, the others, there was a couple of others there on the SEMA world that are more, you know, like some of the EMANATE genes, where you get up in the tens of thousands, but...
Hi, Phil Nadeau from Cowen. Just a couple of follow-up questions. First, on DAYBREAK. David, could you go into your thinking of how you're gonna evaluate the part 2 data to decide which gene touch to take forward in a bit more detail? So it sounds like piecing together your comments, patient population, response rate, and depth of response are three key variables. How do you fit those together as you evaluate what to take forward versus what to deprioritize? And then second, on 718, you mentioned longer IP. Could you give us some sense of how long the composition of matter patent there could last? Thanks.
Yeah. Yeah. Let me take that second one first. So the, the composition of matter is, out to 2041, so that is composition of matter. It's not the formulation. For the, the setmelanotide weekly formulation, that was a formulation patent, is a formulation patent out to 2038. So it's the strength of the patent is, is obviously, stronger by virtue of being a composition of matter. So how do we think about, yeah, the part 2 data? It's just, it's, it's, it's more data. I mean, it's, it's not that, that's gonna dramatically, I think, increase. It'll be more data. So how will it be more data? So those patients that get randomized, who stay on their current, stay on setmelanotide, right? Don't get randomized placebo. We'll just have much longer data and see if they do continue to deepen.
That'll be a huge clue. This is only 14 weeks, so it's still a relatively short period of time, and some of those patients had a dramatic response in a short period. Some are around 5, which could be, you know, still very interesting. So the deepening in terms of those patients who stay on the withdrawal, it's gonna be a little bit challenging 'cause the numbers are so small, and we don't have enough in each cohort to have a strong placebo versus treated for that specific gene. So I think what we're gonna be looking at there more is we're testing the trial design almost as much as we're testing individual genes. So we'll be able to look at patients in all of the treated versus all the placebo withdrawal and say: Did the trial design work?
Because the FDA didn't love this trial design when we first proposed it. So I-- we're taking a second shot at it here in a sense, but that'll be, I think, a really important part. And then third, which is not related to part two, but it's just, you know, the work that Patrick's doing and continuing. I mean, I think you saw, I mean, he gave three examples, you know, and some it's like, you know, just have we learned more about the variant that allows you to reclassify it? That TBX example he gave, which is... That's just saying, "Look, this is where it's located in the gene. We know this is the important part of the gene," and suddenly, you know, we-- it begins to explain why you might have one or the other. The variable penetrance, right?
So here you have a gene where they were both in the responder and the non-responder... How does that work? Maybe it's not important, but if it's clearly documented that you have variable penetrance, you now have an explanation for this. So, and then the last thing I'll say, whatever we take forward, the bar is high. I mean, we're not, we're not looking to take forward something that's just 5%. We need to have some level of conviction that, you know, for these patients, it's really moving the needle in a way that other possible therapies couldn't for them.
Hi, David. Dae Gon from Stifel. Three questions, one on DAYBREAK. Just following up on Phil's question. When we think about the variants that you will identify that will most likely benefit from the setmelanotide treatment, can you talk to us a little bit about your confidence level, that if you were to pursue, continue into phase 3 and show positive benefit, that it would include the entire gene rather than the label, kind of narrowing it down to here are the particular, I guess, variants that are more likely to benefit versus those that are not? In terms of 718-
Actually, let me take that question before you run your list there. It'll be easier. So the label—go back to our EMANATE trial. In our EMANATE trial, we've basically already done that. So for the POMC heterozygote group, we narrowed that group to suspected pathogenic, likely pathogenic, and pathogenic. If you remember from Patrick's graph there. So we've enriched that population, in theory, for those patients who would be most likely to respond. The label will be exactly that. So we won't get a label that will be for all hets. Now, my view is, I don't want a label for all hets. I mean, that's where it becomes really challenging because you've got a drug out there where, you know, some patients are responding, some aren't. The community loses confidence. They don't really know how to use it.
I mean, every drug, you're trying to get to that point where ideally 100% of the patients meet the definition, get the drug, and respond. So yes, it'll be, it'll be the label that reflects our variant piece of it.
If I can just add to that. So in terms of diagnosis, if you think about this from the other side, about how a clinical lab would diagnose a patient, they would do it based off of the pathogenicity of the variants, right? So when you think about it, we're basically including all of these patients based off of the URO data, which is a sequencing effort. But in future, a lab will actually diagnose a patient with a variant if it's, who's suspected pathogenic, pathogenic, or likely pathogenic. So it'll exactly match the label. So all of that information will feed into... You know, that's why I was talking about why it's important to actually have the information to reclassify ACMG variants in the first place.
It's because that's how you're going to identify and diagnose your patients in future, and it'll match the label.
And then, on 718, the comparison between 718 and the setmelanotide in two different mouse models, it seems to show this sort of a, I guess, like a dip at before it kind of picks back up towards the end. But you only showed one dose level for the setmelanotide. So I'm just wondering, what's the maximal degree of benefit you can see with the daily setmelanotide? And 'cause I guess ultimately, you're testing, what, 10 mg-40 mg tentatively in the hypothalamic HO patient. So how much confidence do you guys have there? And then just to quickly tack on that, in the slide, you mentioned it's going to be an efficient development plan. Can you elaborate on that a little bit?
All good questions. Thank you. All good questions. Thank you. So, the first study, which I'll show you, where we compared daily set with the daily 718, it was one of those proof of the concept study, where a single dose was tested. And we pretty much show that with the same dose of 0.5 mg per kg, we see the same reduction, around 9%. But what I show you subsequently, pretty much in my genetic obesity model, with the higher doses, you can see further reduction in body weight and food intake, and it's dose dependent. However, you have to remember, these are the animal models. The first animal model is pretty much model of general obesity, and usually, an MC4 agonist work the best in the obese genetic population because we are restoring this MC4 pathway.
So, what was shown in the study in the Zucker rat model, which is a genetic model of obesity with leptin receptor deficiency, we show you with RM-718 that the higher dose had the bigger effect in body weight reduction, and I will expect the same thing to see with setmelanotide. But again, you don't wanna pretty much. You wanna give the dose which will reduce this hyperphagia, but still, they need to have normal, healthy food intake. Very important for growing kids. That's the first question answered, I hope. And the second one, I'm not clinician, so I think the design, which was pretty much now in plan, is to address safety and PK and tolerability in obese healthy subject.
We are going slowly, increasing the doses between a 3 mg-40 mg, which give us, and we have a nice safety margin. Remember, this is a weekly formulation, so based on these PK results from this study and changes in the body weight, hopefully in hypothalamic obesity patients, we'll be able to then really learn what is the therapeutic dose. Maybe.
No, no, that's perfect. I think the most efficient part of this is the hypothalamic obesity part of the model, which we didn't have for setmelanotide in the beginning. You know, it's such a sensitive readout. You know, the hope is that even in that small trial, part C, we will be able to sort out the dose. I'm less concerned that it won't work. I think it'll work. The question is, how quickly can we get to the dose? That's what we're looking for. Excellent. Well, with that, we'll thank everybody for showing up, showing interest here, and look forward to updating you further. Thanks a lot.